rs1555515731

Positions:

• chr16-68812188-GT-G
• chr16-68812188-GT-GTT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5_Supporting PVS1 PM2_Supporting PS4_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1064delT p.(Leu355Terfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID:16061854). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA336431/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 0.209

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1064del	p.Leu355Ter	frameshift_variant	8/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1064del	p.Leu355Ter	frameshift_variant	8/15		NP_001304113.1
CDH1	NM_001317185.2	c.-552del		5_prime_UTR_variant	8/16		NP_001304114.1
CDH1	NM_001317186.2	c.-756del		5_prime_UTR_variant	8/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1064del	p.Leu355Ter	frameshift_variant	8/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:3

Pathogenic, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Oct 01, 2016	Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 32 year old male with gastric cancer, bladder cancer and colon polyps. Family history of gastric cancer and colon polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 12, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 23, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 224528). This variant is also known as c.1063del. This premature translational stop signal has been observed in individual(s) with gastric, stomach, and bladder cancer (PMID: 16061854, 26845104). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu355*) in the CDH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 04, 2020	This variant deletes 1 nucleotide in exon 8 of the CDH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with diffused gastric cancer (PMID: 16061854) and another individual affected with stomach cancer described as a single focal tumor (PMID: 19269290). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 03, 2021	The c.1064delT pathogenic mutation, located in coding exon 8 of the CDH1 gene, results from a deletion of one nucleotide at nucleotide position 1064, causing a translational frameshift with a predicted alternate stop codon (p.L355*). This mutation, designated as c.1063del, has been previously reported in an individual diagnosed with diffuse gastric cancer at 27 years of age (Suriano G et al. Clin. Cancer Res., 2005 Aug;11:5401-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -

CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 25, 2023

The c.1064delT p.(Leu355Terfs) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 16061854). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_Supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.40		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.40		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555515731; hg19: chr16-68846091;